Immune Mechanisms in Hypertension.

It is now apparent that immune mediators including complement, cytokines, and cells of the innate and adaptive immune system contribute not only to blood pressure elevation but also to the target organ damage that occurs in response to stimuli like high salt, aldosterone, angiotensin II, and sympathetic outflow. Alterations of vascular hemodynamic factors, including microvascular pulsatility and shear forces, lead to vascular release of mediators that affect myeloid cells to become potent antigen-presenting cells and promote T-cell activation. Research in the past 2 decades has defined specific biochemical and molecular pathways that are engaged by these stimuli and an emerging paradigm is these not only lead to immune activation, but that products of immune cells, including cytokines, reactive oxygen species, and metalloproteinases act on target cells to further raise blood pressure in a feed-forward fashion. In this review, we will discuss these molecular and pathophysiological events and discuss clinical interventions that might prove effective in quelling this inflammatory process in hypertension and related cardiovascular diseases.

Fundamental Neurochemistry Review: At the intersection between the brain and the immune system: Non-coding RNAs spanning learning, memory and adaptive immunity.

Non-coding RNAs (ncRNAs) are highly plastic RNA molecules that can sequester cellular proteins and other RNAs, serve as transporters of cellular cargo and provide spatiotemporal feedback to the genome. Mounting evidence indicates that ncRNAs are central to biology, and are critical for neuronal development, metabolism and intra- and intercellular communication in the brain. Their plasticity arises from state-dependent dynamic structure states that can be influenced by cell type and subcellular environment, which can subsequently enable the same ncRNA with discrete functions in different contexts. Here, we highlight different classes of brain-enriched ncRNAs, including microRNA, long non-coding RNA and other enigmatic ncRNAs, that are functionally important for both learning and memory and adaptive immunity, and describe how they may promote cross-talk between these two evolutionarily ancient biological systems.

Immune System and Microvascular Remodeling in Humans.

Low-grade inflammatory processes and related oxidative stress may have a key role in the pathogenesis of hypertension and hypertension-mediated organ damage. Innate immune cells, such as neutrophils, dendritic cells, monocytes/macrophages, as well as unconventional T lymphocytes like γδ T cells contribute to hypertension and may trigger vascular inflammation. Adaptive immunity has been demonstrated to participate in elevation of blood pressure and in vascular and kidney injury. In particular, effector T lymphocytes (Th1, Th2, and Th17) may play a relevant role in promoting hypertension and microvascular remodeling, whereas T-regulatory lymphocytes may have a protective role. Effector cytokines produced by these immune cells lead to increased oxidative stress, endothelial dysfunction and contribute to target organ damage in hypertension. A possible role of immune cell subpopulations in the development and regression of microvascular remodeling has also been proposed in humans with hypertension. The present review summarizes the key immune mechanisms that may participate in the pathophysiology of hypertension-mediated inflammation and vascular remodeling; advances in this field may provide the basis for novel therapeutics for hypertension.

Molecular and Cellular Mechanisms Modulating Trained Immunity by Various Cell Types in Response to Pathogen Encounter.

The induction of trained immunity represents an emerging concept defined as the ability of innate immune cells to acquire a memory phenotype, which is a typical hallmark of the adaptive response. Key points modulated during the establishment of trained immunity include epigenetic, metabolic and functional changes in different innate-immune and non-immune cells. Regarding to epigenetic changes, it has been described that long non-coding RNAs (LncRNAs) act as molecular scaffolds to allow the assembly of chromatin-remodeling complexes that catalyze epigenetic changes on chromatin. On the other hand, relevant metabolic changes that occur during this process include increased glycolytic rate and the accumulation of metabolites from the tricarboxylic acid (TCA) cycle, which subsequently regulate the activity of histone-modifying enzymes that ultimately drive epigenetic changes. Functional consequences of established trained immunity include enhanced cytokine production, increased antigen presentation and augmented antimicrobial responses. In this article, we will discuss the current knowledge regarding the ability of different cell subsets to acquire a trained immune phenotype and the molecular mechanisms involved in triggering such a response. This knowledge will be helpful for the development of broad-spectrum therapies against infectious diseases based on the modulation of epigenetic and metabolic cues regulating the development of trained immunity.

Diabetes mellitus exacerbates experimental autoimmune myasthenia gravis via modulating both adaptive and innate immunity.

BACKGROUND: Diabetes mellitus (DM) is a common concomitant disease of late-onset myasthenia gravis (MG). However, the impacts of DM on the progression of late-onset MG were unclear. METHODS: In this study, we examined the immune response in experimental autoimmune myasthenia gravis (EAMG) rats with DM or not. The phenotype and function of the spleen and lymph nodes were determined by flow cytometry. The serum antibodies, Tfh cells, and germinal center B cells were determined by ELISA and flow cytometry. The roles of advanced glycation end products (AGEs) in regulating Tfh cells were further explored in vitro by co-culture assays. RESULTS: Our results indicated clinical scores of EAMG rats were worse in diabetes rats compared to control, which was due to the increased production of anti-R97-116 antibody and antibody-secreting cells. Furthermore, diabetes induced a significant upregulation of Tfh cells and the subtypes of Tfh1 and Tfh17 cells to provide assistance for antibody production. The total percentages of B cells were increased with an activated statue of improved expression of costimulatory molecules CD80 and CD86. We found CD4+ T-cell differentiation was shifted from Treg cells towards Th1/Th17 in the DM+EAMG group compared to the EAMG group. In addition, in innate immunity, diabetic EAMG rats displayed more CXCR5 expression on NK cells. However, the expression of CXCR5 on NKT cells was down-regulated with the increased percentages of NKT cells in the DM+EAMG group. Ex vivo studies further indicated that Tfh cells were upregulated by AGEs instead of hyperglycemia. The upregulation was mediated by the existence of B cells, the mechanism of which might be attributed the elevated molecule CD40 on B cells. CONCLUSIONS: Diabetes promoted both adaptive and innate immunity and exacerbated clinical symptoms in EAMG rats. Considering the effect of diabetes, therapy in reducing blood glucose levels in MG patients might improve clinical efficacy through suppressing the both innate and adaptive immune responses. Additional studies are needed to confirm the effect of glucose or AGEs reduction to seek treatment for MG.

Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity.

Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson's disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.

The methods and advances of adaptive immune receptors repertoire sequencing.

The adaptive immune response is a powerful tool, capable of recognizing, binding to, and neutralizing a vast number of internal and external threats via T or B lymphatic receptors with widespread sets of antigen specificities. The emergence of high-throughput sequencing technology and bioinformatics provides opportunities for research in the fields of life sciences and medicine. The analysis and annotation for immune repertoire data can reveal biologically meaningful information, including immune prediction, target antigens, and effective evaluation. Continuous improvements of the immunological repertoire sequencing methods and analysis tools will help to minimize the experimental and calculation errors and realize the immunological information to meet the clinical requirements. That said, the clinical application of adaptive immune repertoire sequencing requires appropriate experimental methods and standard analytical tools. At the population cell level, we can acquire the overview of cell groups, but the information about a single cell is not obtained accurately. The information that is ignored may be crucial for understanding the heterogeneity of each cell, gene expression and drug response. The combination of high-throughput sequencing and single-cell technology allows us to obtain single-cell information with low-cost and high-throughput. In this review, we summarized the current methods and progress in this area.

Metavariables Resuming Host Immune Features and Nodal Involvement Are Associated with Oncological Outcomes in Oral Cavity Squamous Cell Carcinoma.

Oral cavity squamous cell carcinoma (OSCC) is a common head and neck cancer characterized by a poor prognosis associated with locoregional or distant failure. Among the predictors of prognosis, a dense infiltration of adaptive immune cells is protective and associated with improved clinical outcomes. However, few tools are available to integrate immune contexture variables into clinical settings. By using digital microscopy analysis of a large retrospective OSCC cohort (n = 182), we explored the clinical significance of tumor-infiltrating CD8+ T-cells. To this end, CD8+ T-cells counts were combined with well-established clinical variables and peripheral blood immune cell parameters. Through variable clustering, five metavariables (MV) were obtained and included descriptors of nodal (NODALMV) and primary tumor (TUMORMV) involvement, the frequency of myeloid (MYELOIDMV) or lymphoid (LYMPHOIDMV) peripheral blood immune cell populations, and the density of tumor-infiltrating CD8+ T-cells (TI-CD8MV). The clinical relevance of the MV was evaluated in the multivariable survival models. The NODALMV was significantly associated with all tested outcomes (p < 0.001), the LYMPHOIDMV showed a significant association with the overall, disease-specific and distant recurrence-free survival (p < 0.05) and the MYELOIDMV with the locoregional control only (p < 0.001). Finally, TI-CD8MV was associated with distant recurrence-free survival (p = 0.029). Notably, the performance in terms of survival prediction of the combined effect of NODALMV and immune metavariables (LYMPHOIDMV, MYELOIDMV and TI-CD8MV) was superior to the TNM stage for most of the outcomes analyzed. These findings indicate that the analysis of the baseline host immune features are promising tools to complement clinical features, in stratifying the risk of recurrences.

Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress.

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells' profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

Immune Aging and Immunotherapy in Cancer.

Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.

The Bone Marrow as Sanctuary for Plasma Cells and Memory T-Cells: Implications for Adaptive Immunity and Vaccinology.

The bone marrow (BM) is key to protective immunological memory because it harbors a major fraction of the body's plasma cells, memory CD4+ and memory CD8+ T-cells. Despite its paramount significance for the human immune system, many aspects of how the BM enables decade-long immunity against pathogens are still poorly understood. In this review, we discuss the relationship between BM survival niches and long-lasting humoral immunity, how intrinsic and extrinsic factors define memory cell longevity and show that the BM is also capable of adopting many responsibilities of a secondary lymphoid organ. Additionally, with more and more data on the differentiation and maintenance of memory T-cells and plasma cells upon vaccination in humans being reported, we discuss what factors determine the establishment of long-lasting immunological memory in the BM and what we can learn for vaccination technologies and antigen design. Finally, using these insights, we touch on how this holistic understanding of the BM is necessary for the development of modern and efficient vaccines against the pandemic SARS-CoV-2.

Pathophysiology of COVID-19-associated acute kidney injury.

Although respiratory failure and hypoxaemia are the main manifestations of COVID-19, kidney involvement is also common. Available evidence supports a number of potential pathophysiological pathways through which acute kidney injury (AKI) can develop in the context of SARS-CoV-2 infection. Histopathological findings have highlighted both similarities and differences between AKI in patients with COVID-19 and in those with AKI in non-COVID-related sepsis. Acute tubular injury is common, although it is often mild, despite markedly reduced kidney function. Systemic haemodynamic instability very likely contributes to tubular injury. Despite descriptions of COVID-19 as a cytokine storm syndrome, levels of circulating cytokines are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome with causes other than COVID-19. Tissue inflammation and local immune cell infiltration have been repeatedly observed and might have a critical role in kidney injury, as might endothelial injury and microvascular thrombi. Findings of high viral load in patients who have died with AKI suggest a contribution of viral invasion in the kidneys, although the issue of renal tropism remains controversial. An impaired type I interferon response has also been reported in patients with severe COVID-19. In light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide insights into therapeutic strategies.

Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity.

Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by the lack of a suitable mouse model. We discovered that transient depletion of biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The immune requirements for Mtb control during latency, and the frequency of relapse, were strikingly different depending on how latency was established. TrxB2 depletion resulted in a latent infection that required adaptive immunity for control and reactivated with high frequency, whereas latent infection after BPL depletion was independent of adaptive immunity and rarely reactivated. We identified immune signatures of T cells indicative of relapse and demonstrated that BCG vaccination failed to protect mice from TB relapse. These reproducible genetic latency models allow investigation of the host immunological determinants that control the latent state and offer opportunities to evaluate therapeutic strategies in settings that mimic aspects of latency and TB relapse in humans.

B and T Lymphocyte Densities Remain Stable With Age in Human Cortex.

One hallmark of human aging is increased brain inflammation represented by glial activation. With age, there is also diminished function of the adaptive immune system, and modest decreases in circulating B- and T-lymphocytes. Lymphocytes traffic through the human brain and reside there in small numbers, but it is unknown how this changes with age. Thus we investigated whether B- and T-lymphocyte numbers change with age in the normal human brain. We examined 16 human subjects in a pilot study and then 40 human subjects from a single brain bank, ranging in age from 44-96 years old, using rigorous criteria for defining neuropathological changes due to age alone. We immunostained post-mortem cortical tissue for B- and T-lymphocytes using antibodies to CD20 and CD3, respectively. We quantified cell density and made a qualitative assessment of cell location in cortical brain sections, and reviewed prior studies. We report that density and location of both B- and T-lymphocytes do not change with age in the normal human cortex. Solitary B-lymphocytes were found equally in intravascular, perivascular, and parenchymal locations, while T-lymphocytes appeared primarily in perivascular clusters. Thus, any change in number or location of lymphocytes in an aging brain may indicate disease rather than normal aging.

Role of the Immune Microenvironment in SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) first emerged in December 2019 in Wuhan, China, and has since spread rapidly worldwide. As researchers seek to learn more about COVID-19, the disease it causes, this novel virus continues to infect and kill. Despite the socioeconomic impacts of SARS-CoV-2 infections and likelihood of future outbreaks of other pathogenic coronaviruses, options to prevent or treat coronavirus infections remain limited. In current clinical trials, potential coronavirus treatments focusing on killing the virus or on preventing infection using vaccines largely ignore the host immune response. The relatively small body of current research on the virus indicates pathological responses by the immune system as the leading cause for much of the morbidity and mortality caused by COVID-19. In this review, we investigated the host innate and adaptive immune responses against COVID-19, collated information on recent COVID-19 experimental data, and summarized the systemic immune responses to and histopathology of SARS-CoV-2 infection. Finally, we summarized the immune-related biomarkers to define patients with high-risk and worst-case outcomes, and identified the possible usefulness of inflammatory markers as potential immunotherapeutic targets. This review provides an overview of current knowledge on COVID-19 and the symptomatological differences between healthy, convalescent, and severe cohorts, while offering research directions for alternative immunoregulation therapeutic targets.

Understanding the increased risk of infections in diabetes: innate and adaptive immune responses in type 1 diabetes.

AIMS: Patients with diabetes have a higher incidence of infections with Candida albicans, Staphylococcus aureus and Mycobacterium tuberculosis, yet factors contributing to this increased risk are largely unknown. We hypothesize that altered innate and adaptive immune responses during diabetes contribute to an increased susceptibility to infections. MATERIALS AND METHODS: We studied cytokine responses to ex vivo pathogenic stimulations in a cohort with type 1 diabetes (n = 243) and non-diabetic healthy control subjects (n = 56) using isolated peripheral blood mononuclear cells (PBMCs). Clinical phenotypical data including BMI, duration of diabetes, and HbA1c levels were collected and related to the cytokine production capacity. RESULTS: Adjusted for age, sex and BMI, the presence of diabetes was associated with significantly lower IL-1ß, IL-6, TNF-α, and IL-17 production upon ex vivo stimulation of PBMCs with C. albicans and S. aureus (all, p < 0.05). In response to stimulation with M. tuberculosis only IL-17 (p < 0.001) was lower in patients with diabetes. Patients with the shortest diabetes duration had a significant lower IL-1ß, IL-6 and TNF-α production (all, p < 0.01) after M. tuberculosis stimulation. Older patients had a significant lower IFN-γ (p < 0.05) production after stimulation with all three pathogens. HbA1c levels and BMI had no significant impact on cytokine production. CONCLUSIONS: PBMCs of patients with type 1 diabetes demonstrate significantly lower cytokine production in response to stimulation with several pathogens, which likely explain, at least in part, the increased susceptibility for these infections.

The role of probiotics and postbiotics in modulating the gut microbiome-immune system axis in the pediatric age.

The complex microbial community of the gut microbiome plays a fundamental role in driving development and function of the human immune system. This phenomenon is named the gut microbiome-immune system axis. When operating optimally, this axis influences both innate and adaptive immunity, which orchestrates the maintenance of crucial elements of host-microorganisms symbiosis, in a dialogue that modulates responses in the most beneficial way. Growing evidence reveals some environmental factors which can positively and negatively modulate the gut microbiome-immune system axis with consequences on the body health status. Several conditions which increasingly affect the pediatric age, such as allergies, autoimmune and inflammatory disorders, arise from a failure of the gut microbiome-immune system axis. Prenatal or postnatal modulation of this axis through some interventional strategies (including diet, probiotics and postbiotics), may lead to a positive gene-environment interaction with improvement of immune-modulatory effects and final positive effect on human health. In particular probiotics and postbiotics exerting pleiotropic regulatory actions on the gut-microbiome-immune system axis provide an innovative preventive and therapeutic strategy for many pediatric conditions.

Targeting immune cell metabolism in kidney diseases.

Insights into the relationship between immunometabolism and inflammation have enabled the targeting of several immunity-mediated inflammatory processes that underlie infectious diseases and cancer or drive transplant rejection, but this field remains largely unexplored in kidney diseases. The kidneys comprise heterogeneous cell populations, contain distinct microenvironments such as areas of hypoxia and hypersalinity, and are responsible for a functional triad of filtration, reabsorption and secretion. These distinctive features create myriad potential metabolic therapeutic targets in the kidney. Immune cells have crucial roles in the maintenance of kidney homeostasis and in the response to kidney injury, and their function is intricately connected to their metabolic properties. Changes in nutrient availability and biomolecules, such as cytokines, growth factors and hormones, initiate cellular signalling events that involve energy-sensing molecules and other metabolism-related proteins to coordinate immune cell differentiation, activation and function. Disruption of homeostasis promptly triggers the metabolic reorganization of kidney immune and non-immune cells, which can promote inflammation and tissue damage. The metabolic differences between kidney and immune cells offer an opportunity to specifically target immunometabolism in the kidney.

Immune Modulatory Activities of Arginyl-Fructose (AF) and AF-Enriched Natural Products in In-Vitro and In-Vivo Animal Models.

The immune system plays an important role in maintaining body homeostasis. Recent studies on the immune-enhancing effects of ginseng saponins have revealed more diverse mechanisms of action. Maillard reaction that occurs during the manufacturing processes of red ginseng produces a large amount of Amadori rearrangement compounds (ARCs), such as arginyl-fructose (AF). The antioxidant and anti-hyperglycemic effects of AF have been reported. However, the possible immune enhancing effects of non-saponin ginseng compounds, such as AF, have not been investigated. In this study the effects of AF and AF-enriched natural product (Ginofos, GF) on proliferation of normal mouse splenocytes were evaluated in vitro and male BALB/c mice models. The proliferation of splenocytes treated with mitogens (concanavalin A, lipopolysaccharide) were further increased by addition of AF (p < 0.01) or GF (p < 0.01), in a dose dependent manner. After the 10 days of oral administration of compounds, changes in weights of spleen and thymus, serum immunoglobulin, and expression of cytokines were measured as biomarkers of immune-enhancing potential in male BALB/c mice model. The AF or GF treated groups had higher weights of the thymus (0.94 ± 0.25 and 0.86 ± 0.18, p < 0.05, respectively) than that of cyclophosphamide treated group (0.59 ± 0.18). This result indicates that AF or AF-enriched extract (GF) increased humoral immunity against CY-induced immunosuppression. In addition, immunoglobulin contents and expression of cytokines including IgM (p < 0.01), IgG (p < 0.05), IL-2 (p < 0.01), IL-4 (p < 0.01), IL-6 (p < 0.01), and IFN-γ (p < 0.05) were also significantly increased by supplementation of AF or GF. These results indicate that AF has immune enhancing effects by activation of adaptive immunity via increase of expression of immunoglobulins and cytokines such as IgM, IgG, IL-2, IL-4, IL-6 and thereby proliferating the weight of thymus. Our findings provide a pharmacological rationale for AF-enriched natural products such as ginseng and red ginseng that can possibly have immune-enhancement potential and should be further evaluated.

Lack of Cell Cycle Inhibitor p21 and Low CD4+ T Cell Suppression in Newborns After Exposure to IFN-ß.

Type I IFNs, such as interferon alpha and interferon beta, are key regulators of the adaptive immune response during infectious diseases. Type I IFNs are induced upon infection, bind interferon α/ß receptors on T-cells and activate intracellular pathways. The activating and inhibitory consequences of type I IFN-signaling are determined by cell type and cellular environment. The neonatal immune system is associated with increased vulnerability to infectious diseases which could partly be explained by an immature CD4+ T-cell compartment. Here, we show low IFN-ß-mediated inhibition of CD4+ T-cell proliferation, phosphorylation of retinoblastoma protein and cytokine production in human newborns compared to adults. In addition, both naïve and total newborn CD4+ T-cells are unable to induce the cell-cycle inhibitor p21 upon exposure to IFN-ß in contrast to adults. The distinct IFN-ß-signaling in newborns provides novel insights into T cell functionality and regulation of T cell-dependent inflammation during early life immune responses.